Good manufacturing practices (gmp) for pharmaceutical excipients
Good Manufacturing Practices
(GMP) for Pharmaceutical
K.SHANTHA KUMARI MAM
NIRMALA COLLEGE OF PHARMACY
DEPT. OF PHARMACEUTICAL ANALYSIS
The principles outlined in this Standard provide a
comprehensive basis for the quality management
system used in the manufacture of pharmaceutical
excipients. Implementation of these principles shall
result in the achievement of three main objectives
a) Achieve excipient realization – the organization shall
implement and maintain a system that delivers
excipients with the quality attributes necessary to
meet the requirements and expectations of customers,
pharmaceutical users, and regulatory authorities,
b) Establish and maintain a state of control – the
organization shall ensure the manufacture and supply
of excipients is in accordance with this Standard, thus
providing customers with some assurance of
continued suitability and reliability of supply, and
c) Facilitate continual improvement – the organization
shall collect objective evidence to continually develop
and enhance the application of these quality
management system principles to further assure
This Standard is intended to define Good
Manufacturing Practices (GMP) for excipient
manufacture for use in drug products.
It sets minimum requirements for GMP applicable to
This Standard includes the critical elements of a
quality management system for excipient
and the GMP principles in the IPEC-PQG Good
Manufacturing Practices Guide for Pharmaceutical
Excipients impact the appearance, stability, and
delivery of drug products and are essential to the
safety, quality, and efficacy of these products.
Testing of excipients cannot ensure detection of the
myriad of possible contaminants and functional
deficiencies from poor excipient manufacturing
practices that may result in a finished drug product
that is ineffective or adversely affects patient health.
Quality Management System
General Requirements: The organization shall
document, manage, and implement the quality
management processes and GMP required to assure
The organization shall maintain and continually
improve the quality management system and GMP
in accordance with the requirements of this
General Quality Management
1.Define individual and collective roles, responsibilities,
authorities and inter-relationships of all organizational units
related to the excipient quality management system ensure
these interactions are communicated and understood at all
relevant levels of the organization.
2.Define the interactions of the processes stated herein, with
the operations needed for the quality management system and
the implementation of GMP.
3.Determine the criteria and methods to ensure that the
operation and control of these processes and GMP are
where manufacturing testing, or other operations
that may affect excipient quality are outsourced, the
a) Define the responsibility for quality and the control
measures within the quality management system.
b) Demonstrate that the applicable GMP principles in
accordance with this Standard are applied to those
The organization shall define and document the point
in the manufacture and supply of the excipient at
which the full requirements8 of this Standard apply.
General: The design, organization, and
documentation of the quality system shall be
structured to facilitate common understanding and
The use of appropriate quality risk management
principles shall be incorporated into the design of
the quality management system.
The organization shall prepare a Quality Manual describing
the quality management system, the Quality Policy, and the
commitment of the organization to apply the GMP and quality
management requirements contained in this Standard. The
Quality Manual shall also include:
a) The scope of the quality management system
b) Reference(s) to supporting procedures
c) A description of the interaction between quality
management processes and
d) Identification of the point at which GMP as described
herein is applied to the organization’s manufacturing
Control of Documents: Documents required by this
Standard and those determined by the organization as necessary
to implement GMP and the quality management system shall be
controlled. Records are a special type of document and shall be
controlled according to the requirements
a) approve documents for adequacy by designated
personnel prior to issue
b) periodically review, update as necessary, and reapprove documents,
c) ensure that documents remain legible and readily
e) ensure that documents remain legible and readily
Control of Records:
The organization shall establish and maintain a documented
procedure for the identification, collection, indexing, filing,
storage, maintenance, protection, retention time, and
disposition of records.
Records shall be established and maintained to demonstrate
achievement of the defined specifications and conformance
with this Standard
The record retention period shall not be less than three years
past the excipient’s expiry or first reevaluation date.
Top management shall ensure the integrity of the quality
management system is maintained when changes are
planned and implemented.
There shall be a documented procedure for the evaluation
and approval of changes that may impact upon the quality
of the excipient, including the impact on any regulatory
submissions by the excipient manufacturer.
The evaluation and approval of planned changes shall
occur prior to the implementation of the changes.
Management Commitment: Top management shall
have the responsibility to:
a) ensure an effective excipient quality management system
is in place to achieve the Quality Objectives and that roles,
responsibilities, and authorities are defined,
communicated, and implemented
b) communicate to the organization the importance of
conforming to the Quality Policy and support achievement
of the Quality Objectives
c) provide evidence of its commitment to meeting the
requirements of this Standard, the relevant statutory and
regulatory requirements, and customer expectations
Customer Focus: It is the responsibility of top
management to ensure customer key requirements are
identified, established and met.
Quality Policy: Top management shall establish a quality
policy that describes the overall intentions and direction of the
organization related to quality. The Quality Policy shall:
a) include commitments to implementation of GMP,
compliance with applicable regulatory requirements, and
b) be communicated to and understood by personnel at all
levels in the organization
c) be reviewed at a defined frequency for continuing
Top management shall ensure Quality Objectives are
established for relevant functions and levels within the
organization for adherence to this Standard. The
organization shall maintain, regularly review, and
demonstrate its performance against Quality Objectives.
Quality Objectives shall be deployed through out the
organization and shall be understood, measurable, and
consistent with the Quality Policy.
Quality Management System Planning: Top
management shall provide adequate resources to
ensure conformance to the provisions of this
Standard. There shall be a process for the
identification of resources needed for adherence to
A gap analysis based on audits by internal personnel,
customers, regulatory agencies, or outside
contractors to this Standard may be used for the
purpose of identifying resource requirements..
Responsibility, Authority, and
Responsibility and Authority:
a) approving suppliers of quality-critical materials, components,
b) approving or rejecting quality-critical materials and
c) implementing an internal audit program of the quality
d) approving the results of investigations into deviations from
process instructions, test or measurement failures, and
reviewing and authorizing changes to processes, specifications,
procedures, and test methods that may affect excipient quality
Internal Communication: The organization
shall ensure appropriate systems are established
to communicate throughout the organization the
requirements of this Standard and applicable
regulatory requirements. The communication
shall also provide information about the
effectiveness of the excipient quality
Top management shall be notified in a timely
manner of quality-critical situations in
accordance with a documented procedure.
Top management shall hold scheduled reviews of the
excipient quality management system to confirm
continued conformance to this Standard. The review
shall be documented. Any opportunities for
improvement shall be assessed and implemented via
the change control procedure
The management review inputs shall include, at a
minimum, performance metrics and trends for:
a) action items from the previous management review,
b) results of internal and external audits,
c) excipient conformity and process performance,
d) customer feedback regarding the organization’s
e) customer complaints,
f) status and review of corrective and preventive actions,
g) changes to the excipient quality management system.
The management review shall identify the
resources needed and opportunities presented for
improvement of the quality management system
and improvement of excipient conformance to
customer and regulatory requirements. A record
shall be made of all actions ordered and taken.
Provision of Resources:
The organization shall provide sufficient resources
and qualified personnel to implement and
continually improve the excipient quality
management system and to manufacture, package,
test, store, and release each excipient batch in a
manner consistent with this Standard.
The infrastructure shall be operated, cleaned, and
maintained in accordance with this Standard to
ensure excipient quality. There shall be adequate
facilities for the relevant activities conducted at the
Buildings and Facilities:
Contamination prevention shall be considered in
the design, maintenance, refurbishing, or
upgrading of buildings and facilities.
a) state of repair of the building and facility,
b) suitable size, construction, and location,
c) ability to maintain a suitably clean building and
Equipment used in the production, processing,
packaging, testing, or storage of an excipient shall
a) maintained in a good state of repair,
suitable size, construction, and location to facilitate
cleaning, maintenance, and correct operation,
commensurate with the type of processing.
c) constructed so contact surfaces will not be
reactive, additive, or absorptive.
New installations or replacement equipment shall
be designed to minimize the possibility of
contamination and shall undergo planned activity
before use to ensure it is functioning as intended.
The organization’s procedures and associated
schedules for equipment maintenance shall be
established for the maintenance of quality-critical
equipment used in the production, processing,
packaging, testing, and holding of the excipient.
There shall be records of the use, maintenance, and
associated cleaning of quality-critical equipment.
good practice in production
The organization shall conduct a risk assessment
considering the risk to excipient quality from
utilities (nitrogen, compressed air, steam, etc.) used
in the production, storage, or transfer of materials.
Appropriate action shall be taken to control the risk
to excipient quality.
Water: Water coming into direct contact with the
excipient, intermediate, or excipient contact surfaces
shall have documented specifications. Unless otherwise
justified, water shall, at a minimum, meet the WHO
Guidelines for Drinking-Water Quality.
Where water used in the process is treated by the
organization to achieve a defined quality, the treatment
process shall be specified and the quality of the water
monitored and controlled within specified limits.
The organization shall conduct a risk assessment
based on intended route of administration of the
dosage form to identify areas in which the excipient
is at risk for contamination from exposure to the
work environment. Controls shall be applied to
maintain a suitable environment to minimize the risk
to excipient quality.
The work environment shall be managed and
controlled to minimize risks of excipient
contamination. A documented risk assessment shall
be carried out to determine the necessary controls.
The documented risk assessment shall consider the
following controls, as applicable:
a) air handling systems,
b) special environments,
c) cleanliness and sanitary conditions,
d) waste segregation and disposal,
e) pest control, and
f) personnel hygiene.
Where maintenance of the work environment is
critical to excipient quality, the controls shall be
Where the risk assessment has identified that an
air handling system poses a potential risk to
excipient quality, the air handling system shall be
designed and maintained to assure adequate
protection of the excipient. The organization shall
demonstrate its effectiveness.
Cleaning and Sanitary Conditions:
Where the risk assessment has identified that clean
and/or sanitary conditions of the work environment
are necessary to protect excipient quality, the
organization shall document procedures assigning
responsibility for cleaning and/or sanitation.
Cleaning and/or sanitization records shall be
Planing of Excipient Realization:
The organization shall plan and develop the
processes and controls needed for excipient
Including implementation of identified actions from
risk assessments described in other sections of this
These plans and controls shall be appropriate to the
production process, including subcontractor
Activities, and include.
a) Equipment and facilities for storage and testing
used in the manufacture and supply of the excipient.
b) Testing programs for quality-critical materials
and the finished excipient that include appropriate.
specifications, sampling plans, and test and release
c) Environmental and hygiene control programs to
minimize contamination of the excipient.
The record system shall demonstrate these
processes and controls were followed.
The use of recycled or recovered materials
containing recoverable amounts of excipient,
reactants, or Intermediates shall be justified.
Determination of Requirements Related to
The organization shall determine the excipient
quality, labeling, legal, and regulatory requirements,
as well as those provided by the customer.
Requirements not stated by the customer but
necessary for the specified or intended use, where
known, shall be considered.
Changes requiring notification and/or documented
prior approval from the customer shall be
Review of Requirements Related to the
The organization shall review the requirements
identified in to assure the facilities .
processes are capable of consistently meeting
these requirements and shall document the
review and agreement with the customer before
Where the requirements determined in are
changed, this review shall be repeated before
The organization shall establish a system for
selecting, approving, and reapproving suppliers of
materials and services.
Quality-critical materials and services shall be
identified from risk assessments.
The organization shall communicate purchasing
information to approved suppliers.
The purchasing information shall describe the
material or service ordered .
Verification of Purchased Product:
The organization shall establish procedures
describing the verification, approval, and release
of all purchased material used for excipient
manufacture and packaging.
Production and Service Provision
Control of Production and Service Provision:
The organization shall conduct excipient production activities in
accordance with the following:
a) production instructions that describe the manufacture of the
excipient and that establish records.
providing sufficient detail to ensure the following:
i) the excipient was manufactured and packaged according to the
ii) the time and date of quality-critical activities performed,
iii) the identification of individuals performing such activities,
iv) the traceability of materials (including recycled and recovered
v) the identification and traceability of equipment used,
maintenance, and cleaning.
Validation of Processes for Production and
The organization’s excipient quality management
system shall provide ongoing evidence that the
processes are capable of consistently achieving the
desired quality outcome based on knowledge of
process parameters, excipient attributes, and their
Measurement, Analysis and Improvement
The organization shall plan and implement the
monitoring, measurement, and improvement
activities required to demonstrate conformity of the
excipient to customer requirements and to ensure
conformity of the quality management system to this
Monitoring and Measurement:
The organization shall carry out a comprehensive
system of planned, scheduled, and documented
internal quality audits.
Audits shall be conducted by qualified individuals
independent of the area being audited according to
documented procedures that include, at a minimum,
a) determination of the effectiveness of quality
b) compliance with procedures and processes
described by the quality management system.
Monitoring and Measurement of Processes:
The organization shall identify the tests and
measurements necessary to adequately control the
manufacturing and quality of the excipient.
Monitoring and Measurement of Product:
The organization shall establish and document the
test methods and procedures used to verify the
excipient meets specifications.
Laboratory Controls and Records:
Laboratory controls shall include complete data derived from tests necessary to verify
conformance with specifications and standards including:
a) A description of the sample received for testing together with the material name, batch
number, other distinctive code, and date the sample was taken.
b) Documentation of sample preparation in conformance with test requirements.
c) A statement referencing each test method used.
d) A record of raw data secured during each test including graphs, chromatograms, charts.
Spectra from laboratory instrumentation, identified to show the specific material and batch
e) A record of calculations performed in connection with the test.
f) Test results and how they compare with established specifications.
g) A record of the person who performed each test and the date(s) the tests were performed.
Finished Excipient Testing and Release:
Appropriate measures for verification of excipient
quality shall be performed to confirm that the
conforms to documented specifications. Records shall
confirm excipient's produced by continuous processes
conform to specifications as shown through the results
of in-process testing, other process control records,
finished package testing, etc.
Certificates of Analysis: The Certificate of Analysis shall
include, at a minimum:
a) Excipient name and, if applicable, grade and compendial
b) Manufacturer’s name and site of manufacture,
c) Date of manufacture,
d) Batch number,
e) Expiration or retest date,
f) Statement of compliance to the required specifications,
g) Statement of compliance to GMP as defined by this Standard.
h) Analytical results specific to the batch, unless otherwise noted
i) Acceptance criteria.
j) Analytical method reference.
k) Name and title of person authorizing the Certificate of
Stability and Expiry/Retest Periods:
The stability of the excipient shall be documented.
The stated stability of the excipient shall be
a) historical data, and/or
b) on-going stability studies
Analysis of Data:
The organization shall define methods for evaluating.
a) The effectiveness of its quality management system.
b) The ability to consistently produce conforming
c) Trending of excipient nonconformance with this
Standard, customer complaints, etc.
The organization shall periodically review, including
data from and improve manufacturing and quality
management system processes.
Preventive Action: The organization shall establish
a) Initiating preventive actions commensurate with
the corresponding risks.
b) Implementing and recording changes in procedures
and processes resulting from preventive action.
c) Ensuring the effectiveness of preventive actions.
European Commission, Committee for Proprietary Medicinal Products,
CPMP/QWP/1529/04 Guideline on control of Impurities of
Pharmacopoeial Substances, April 2004
Rules and Guidance for Pharmaceutical Manufacturers and Distributors,
Medicines and Healthcare products Regulatory Agency, 2002
European Commission, Committee for Proprietary Medicinal Products,
The Rules Governing Medicinal Products in the European Union, Volume
4, Good Manufacturing Practices
International Pharmaceutical Excipients Council Good Manufacturing
Practices Guide For Bulk Pharmaceutical Excipients, 2001.
International Pharmaceutical Excipients Council of the Americas Good
Manufacturing Practices Audit Guideline for Bulk Pharmaceutical